There are many factors which influence the addictiveness of a drug. The route of administration is a major determinant of the speed of drug entry into the body and to receptors in the central nervous system which produce resultant effects. Clinical studies are in progress which determine the importance of different routes of administration and the relationship of blood concentrations of drug and active metabolites to concomitant drug effects. Studies of heroin, cocaine and marijuana administration by the intravenous, smoked, intranasal (heroin and cocaine) and oral routes are underway or have been performed. New initiatives include an evaluation of the consequences of chronic cocaine use and cocaine withdrawal. Concurrent physiological, behavioral and performance measures are collected along with blood specimens. Blood specimens are analyzed for drug and metabolites by solid phase extraction-gas chromatography/mass spectrometry. The intravenous and smoked routes produce a rapid onset of pharmacologic effects together with an early appearance of drug and metabolites in blood. It is evident that the smoking route enables individuals to obtain similar pharmacologic effects as produced by intravenous administration of drug, but without the trauma of needle use. Physiological measures such as pupil diameter were compared to drug and metabolite blood levels. Evidence of delays in distribution to effector sites are observed following marijuana smoking, but drug effects following heroin and cocaine administration coincided more closely with concurrent blood concentrations. Onset to effects are delayed longer following intranasal administration and became pronounced after oral administration.